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Off-label ketamine for treatment resistant depression

About 30% of people with depression do not respond to standard antidepressant trials, and there is a huge current need for more effective treatments. Depression remains a leading cause of global disability, and there have been few major advances for treatment-resistant depression (TRD). Currently, there is no antidepressant nearly as effective as ECT, discovered around a century ago. One of the most important breakthroughs at the turn of the century was the demonstration of the rapid antidepressant effect of the anesthetic ketamine. Recently, in August of 2025, Norway became the first country in the world to offer public reimbursement on a national level for off-label ketamine for treatment resistant depression.



A history of the use of ketamine for depression in Norway


Ketamine, primarily an NMDA receptor antagonist, was synthesized in 1962 and approved as an anesthetic in the United States in 1970. Shortly after, it gained widespread use in pain management during the Vietnam War, and became one of the most widely used medications, currently on the WHO list of essential medicines. One of the benefits over other anesthetics is that it can induce anesthesia without affecting airway reflexes, breathing or causing hypotension - making it a very useful medicine for young, elderly, and those with comorbidities. At subanesthetic doses, ketamine causes an altered state of consciousness with altered perceptions, cognition, mood, sense of space and time, and an out-of-body experience while remaining conscious - leading to it being classified as a dissociative anesthetic.


The first documentation of the use of ketamine in psychiatry was in Iran in 1973 (1). Coinciding with the UN ban on psychedelic research, these psychiatrists and another group in Russia turned to the use of ketamine to harness its psychoactive effects for use as an abreactive catalyst for psychotherapeutic change (2). In the US, a separate line of inquiry emerged. Along with general dissatisfaction with the post-marketing effectiveness of the SSRIs, research on the glutamate system in depression and preclinical studies suggested that NMDA antagonists might have an antidepressant effect. In 2000 at Yale, the first randomized controlled trial on ketamine for depression was published, demonstrating a large effect within hours, rather than weeks to months like other antidepressants (3). This work continued at the NIMH and other centers building the evidence base, but without pharmaceutical industry funding to research a generic off-patent medicine, it wasn´t until 2017 that the American Psychiatric Association finally supported the use of ketamine for TRD (4). Since that time, numerous international groups including CANMAT and recently the UK Royal College of Psychiatrists have published similar supportive consensus statements (5,6). To date there are over 50 RCTs and more than 15 meta analyses demonstrating the rapid and robust antidepressant and antisuicidal effect of ketamine for TRD (7).


Many therapeutic mechanisms have been studied, with multiple lines of evidence including induction of neuroplasticity, normalization of functional networks, antiinflammatory effects, down regulation of negative reward, and catalyzation of positive psychological changes mediated by the subjective experience (8). Clinical experience and some research data suggests that ketamine treatment combined with concurrent psychotherapy may augment and prolong the therapeutic effects (9).


Ketamine, primarily an NMDA receptor antagonist, was synthesized in 1962 and approved as an anesthetic in the United States in 1970. 2D structure of ketamine, image by Wikimedia Commons.
Ketamine, primarily an NMDA receptor antagonist, was synthesized in 1962 and approved as an anesthetic in the United States in 1970. 2D structure of ketamine, image by Wikimedia Commons.

In Norway, ketamine was not used in psychiatry until more recently. In 2016, the author established a clinic in the US in New Mexico, and worked with ketamine for depression for several years, witnessing firsthand the often-remarkable rapid remission in patients for which no other treatments had been effective. After initial attempts to start a pilot project in the public health system, a private clinic - Axon, was opened in Oslo to provide patient access pending public availability. The Norwegian Psychiatric Association requested a review of the practice in 2018, and the medical board ruled in 2019 that the clinical practice was a professionally sound off-label treatment based on the currently available evidence.


In 2020, in collaboration with psychiatrist Ingmar Clausen, head of Nordre Østfold DPS, we opened Scandinavia´s first dedicated ketamine unit for the treatment of depression and acute suicidality at Sykehuset Østfold in Kalnes. The unit was moved to an outpatient location at DPS Moss in 2021, where around 500 patients with TRD have since been treated. The majority of patients have had a positive response, with a good safety record. The outcomes will be published in a large observational study underway. Preliminary analyses show that around 60% of treated patients have responded (≥50% reduction in MADRS score) and around 40% achieved full remission (MADRS ≤12). An overview of experience from the public unit was recently published in the Journal of the Norwegian Medical Association, including public access to the standard procedures developed at DPS Moss for the use of ketamine for TRD (10). An important component of this Norwegian protocol is the requirement for the patients to be engaged in concomitant psychotherapy, which we believe increases the likelihood of more durable long-term psychological and behavioural change.


To engage other mental health professionals in research and development on a national level, the Norwegian Rapid Acting Antidepressant Network (NORAAD) was established in 2023, including representative psychiatrists from all health regions nationwide. The network held the first national ketamine conference in Hamar in 2024. Led by psychiatrist Ole Andreassen at the University of Oslo, NORAAD worked together to secure public funding for a multisite RCT with around 200 participants, to fill the knowledge gap about initial dosing schedules and maintenance strategies. Training for the trial has been completed, with several sites already doing clinical treatment, and recruitment is expected to begin in early 2026.


As generic racemic ketamine for TRD remains an off-label indication, the personnel and equipment costs of the treatment (the medication itself is very cheap) needed to be absorbed by the local psychiatric units, so in 2022 a request was made for a health technology assessment (HTA) to consider public reimbursement. In 2024, the Bestillerforum of Nye Metoder (the Norwegian HTA body) formally requested an assessment of ketamine for TRD from the Norwegian Medicines Agency (NoMA), which published its report in June of 2025. The report from the medicines agency concluded in a 170-page report that ketamine is generally well tolerated in patients with treatment-resistant depression and demonstrates better response rates, remission rates, and depression scores compared to saline, midazolam, and ECT at a much lower cost to the health care system (11).


The history of the national implementation of generic ketamine for depression in Norway has also been a testament to the strong Nordic belief in universal health equity: making decisions about what novel methods and medicines we approve based more on rational cost/benefit assessments for our healthcare infrastructure and citizens, rather than only rubber-stamping new arrivals from the traditional pharmaceutical regulatory pathway.

In August the Norwegian Beslutningsforum (decision forum for new methods) ruled positively on the NoMA report, with this decision-making Norway the first country in the world to implement on a national level publicly funded off-label ketamine treatment for treatment-resistant depression. With the Beslutningsforum’s decision, patients across the country can now receive equal access to this health service, at no cost within the public healthcare infrastructure. Under the rules of the decision, public reimbursement requires that ketamine treatment be provided within the specialist mental health services, and that treated patients are enrolled in either data registries or within the setting of a clinical trial. Since reimbursement does not change the off-label status when used for depression, patients must also be informed of and consent for off-label treatment. The decision will be re-evaluated before the end of 2028 and be reviewed with an emphasis on long-term efficacy and safety data.


This development in Norway is important considering the very different response that many European health authorities have had to the on-label medicine Spravato (nasally administered esketamine, the S-enantiomer of ketamine). Spravato was FDA and EMA approved for TRD in 2019, but costs up to 7800 NOK per dose, over 100 x the cost of generic racemic ketamine. So despite EMA approval, it has not received public financing approval in the Norwegian health system, based on health economic analyses like the UK NICE assessment and those of many other European HTAs.


Depression continues to be a challenging disorder to treat, with high comorbidity and impact on quality of life, and we still suffer from a limited availability of highly effective treatment options. Despite high indicators of overall happiness in the Nordics, the prevalence of depression and TRD remains comparable with rates in the global North with no indication of decline. The repurposing of an old previously approved anesthetic with a 55-year history of medical use has added a much needed safe, cheap and effective rapidly-acting antidepressant treatment to our toolbox. The history of the national implementation of generic ketamine for depression in Norway has also been a testament to the strong Nordic belief in universal health equity: making decisions about what novel methods and medicines we approve based more on rational cost/benefit assessments for our healthcare infrastructure and citizens, rather than only rubber-stamping new arrivals from the traditional pharmaceutical regulatory pathway. As we roll out national access to clinical treatment with ketamine for TRD in all health regions, we expect to see an exponential impact for the many patients who continue to suffer despite other available treatments. We also hope that the Norwegian experience can be used as a model for other European health systems to implement this novel treatment to increase accessibility to available therapeutic options for all who might benefit. □


References


  1. Khorramzadeh E, Lofty AO. The use of ketamine in psychiatry. Psychosomatics: Journal of Consultation and Liaison Psychiatry. 1973 Nov.

  2. Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of psychoactive drugs. 1997 Jun 1;29(2):165-83.

  3. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biological psychiatry. 2000 Feb 15;47(4):351-4.

  4. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB, American Psychiatric Association. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA psychiatry. 2017 Apr 1;74(4):399-405.

  5. Bond DJ, Hadjipavlou G, Lam RW, McIntyre RS, Beaulieu S, Schaffer A, Weiss M. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid attention-deficit/hyperactivity disorder. Annals of Clinical Psychiatry. 2012 Feb;24(1):23-37.

  6. Royal College of Psychiatrists (2025) College Position Statement PS02/25 – Psychedelic and related substances for medical use (including pharmacologically assisted psychotherapy)

  7. Nikolin S, Rodgers A, Schwaab A, Bahji A, Zarate C, Vazquez G, Loo C. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023 Aug 1;62.

  8. Lullau AP, Haga EM, Ronold EH, Dwyer GE. Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression. Frontiers in neuroscience. 2023 Aug 8;17:1223145.

  9. Garel N, Drury J, Thibault Lévesque J, Goyette N, Lehmann A, Looper K, Erritzoe D, Dames S, Turecki G, Rej S, Richard-Devantoy S. The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression. Frontiers in Psychiatry. 2023 Sep 19;14:1268832.

  10. Berthold-Losleben M, Autran I, Folstad RL, Römer B, Kvam TM, van de Vooren IT, Stewart LH, Claussen I, Andreassen OA. Ketamine in treatment-resistant depression. Tidsskrift for Den norske legeforening. 2025 Apr 24.

  11. Ohm IK, Flatby AV, Stoinska-Schneider A et al. Intravenøs ketamin ved behandlingsresistent depresjon: en fullstendig metodevurdering. ID2022_018 2025. https://www.nyemetoder.no/49eba4/contentassets/3d24ef749d894a71a1022bfd90de6751/id2022_018-intravenos-ketamin-ved-behandlingsresistent-depresjon_kun-offentlig-versjon.pdf 

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